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There are now over 7 million recognised per- and polyfluoroalkyl substances (PFAS), however the majority of routine monitoring programmes and policy decisions are based on just a handful of these. There is need for a shift towards gaining a better understanding of the total PFAS present in a sample rather than relying on targeted analysis alone. Total PFAS methods help us to understand if targeted methods are missing a mass of PFAS, but they do not identify which PFAS are missing. Non-targeted methods fill this knowledge gap by using high resolution mass spectrometry to identify the PFAS present in a sample. In this manuscript we use complimentary targeted and non-targeted analysis (NTA) to detect hundreds of PFAS in five freshwater samples obtained from the Northwest of the UK. Targeted analysis revealed PFOA at a maximum concentration of 12,100 ng L -1 , over three orders of magnitude greater than the proposed environmental quality standard (EQS) of 100 ng L -1 . A conservative assessment calculated an average total PFAS concentration of approximately 40 μg L -1 across all samples. A suspect screening approach identified between 1175 (least conservative) to 89 (most conservative) PFAS at confidence level 4. Exploratory data analysis was used to identify 33 PFAS at confidence level 3 and 10 PFAS at a confidence level of 2. Only 8 of these 43 PFAS (representing 17% of the total PFAS peak area) are regularly monitored in the UK as part of the UK DWI 47 PFAS. Our results suggested the presence of a novel group of unsaturated perfluoroalkyl ether carboxylic acids (U-PFECAs) related to EEA-NH 4, a perfluoroalkyl ether carboxylic acid (PFECA), providing an example of the benefits of non-targeted screening. This study highlights the merits of non-targeted methods and demonstrates that future monitoring programmes and regulations would benefit from incorporating a non-targeted element., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The synthesis of 9 core-functionalised naphthalene diimide (c-NDI) residues is reported via a 3-step solvent free synthesis from naphthalenetetracarboxylic dianhydride using only mechanochemical activation. Selective dibromination and subsequent dimidiation were achieved for the first time in a vibratory ball mill, resulting in the key structural intermediate, 2,6-dibromonaphthalenediimide (DBND), which is the basis for elaboration into a multitude of organic electronic materials. Our new synthesis of DBND is achieved in just 5 hours' reaction time over two steps compared to typical solution state times of 24 hours. Subsequent Heck-type cross coupling reactions, with a range of styrene residues, produced a series of c-NDIs in good yields. The Heck-type reactions are rapid (1.5 hours), require no additional heating or solvent and are tolerant of atmospheric moisture and air., (© 2024 Wiley‐VCH GmbH.)

Background: Myosteatosis is a measure of skeletal muscle quality that is readily identifiable on computed tomography (CT). The effect of preoperative myosteatosis on outcomes after radical esophagectomy remains unclear. This study aimed to correlate the presence of myosteatosis on CT scan with perioperative morbidity, mortality, and survival outcomes after esophagectomy in an Australian population across 3 esophageal cancer centers., Methods: A retrospective analysis was performed for all patients undergoing radical esophagectomy for cancer across 3 centers. Radiologic assessment of preoperative CT images was performed to determine the presence of myosteatosis. The outcomes measured included perioperative complication rate, overall survival (OS), and disease-free survival (DFS)., Results: A total of 462 patients were included in the analysis (male patients, 78.4%; median age, 67 years). Moreover, 353 patients (76.4%) had myosteatosis on CT. Compared to patients with normal skeletal muscle attenuation, patients with myosteatosis had a higher rate of major (Clavien-Dindo grade ≥ IIIb) complication (14.7% vs 24.9%, respectively; P = .026) and a higher rate of 30-day mortality (0.0% vs 4.0%, respectively; P = .048). Myosteatosis was associated with a major complication on multivariate analysis (hazard ratio, 1.906; 95% CI, 1.057-3.437; P = .032). There was no difference in OS and DFS between patients with and without myosteatosis (OS: 59 vs 56 months, respectively [P = .465]; DFS: 39 vs 42 months, respectively; P = .172)., Conclusion: The presence of myosteatosis on radiologic imaging was associated with an increased risk of major complications and 30-day mortality. Identifying myosteatosis can be an adjunct to preoperative nutritional assessment and prognostication, facilitating early recognition of patients at risk of complications., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background: Newly diagnosed breast cancer patients experience symptoms that may affect their quality of life, treatment outcomes, and survival. Preventing and managing breast cancer-related symptoms soon after diagnosis is essential. The purpose of this study was to investigate the associations between health-related fitness (HRF) and patient-reported symptoms in newly diagnosed breast cancer patients., Methods: This study utilized baseline data from the Alberta Moving Beyond Breast Cancer Cohort Study that were collected within 90 days of diagnosis. HRF measures included peak cardiopulmonary fitness (peak volume of oxygen consumption (VO 2peak )), maximal muscular strength and endurance, flexibility, and body composition. Symptom measures included depression, sleep quality, and fatigue. Adjusted multivariable logistic regression was performed for analyses., Results: Of 1458 participants, 51.5% reported poor sleep quality, 26.5% reported significant fatigue, and 10.4% reported moderate depression. In multivariable-adjusted models, lower relative VO 2peak was independently associated with a greater likelihood of all symptom measures, including moderate depression (p < 0.001), poor sleep quality (p = 0.009), significant fatigue (p = 0.008), any symptom (p < 0.001), and multiple symptoms (p < 0.001). VO 2peak demonstrated threshold associations with all symptom measures such that all 3 lower quartiles exhibited similar elevated risk compared to the highest quartile. The strength of the threshold associations varied by the symptom measure with odds ratios ranging from ∼1.5 for poor sleep quality to ∼3.0 for moderate depression and multiple symptoms. Moreover, lower relative upper body muscular endurance was also independently associated with fatigue in a dose-response manner (p = 0.001), and higher body weight was independently associated with poor sleep quality in an inverted U pattern (p = 0.021)., Conclusion: Relative VO 2peak appears to be a critical HRF component associated with multiple patient-reported symptoms in newly diagnosed breast cancer patients. Other HRF parameters may also be important for specific symptoms. Exercise interventions targeting different HRF components may help newly diagnosed breast cancer patients manage specific symptoms and improve outcomes., (Copyright © 2024. Production and hosting by Elsevier B.V.)

The bacteria in the human colon outnumber the total number of nucleated cells in the human body by approximately 10:1. The DNA that the bacteria contain is enriched around 20-fold in immune stimulatory CpG motifs compared to the DNA of host cells. In addition, this DNA can have alternative more immunogeneic DNA structures and it may be presented to the immune system alongside other proinflammatory bacterial innate ligands such as LPS. To ensure that this immunostimulatory combination is not pathogenic, the luminal boundary of host tissues in the human gastrointestinal tract is protected by cells secreting bactericides together with the secreted enzyme DNASE1L3 that can break down bacterial DNA. Cells with RNA encoding DNASE1L3 are particularly abundant in the gut-associated lymphoid tissue where bacteria are specifically sampled into the body, alongside B cells noted for their T independent function. Importantly, individuals with loss of function mutations in DNASE1L3 develop anti-DNA antibodies and lupus symptoms. In this review, we explore the possibility that a perfect storm might break tolerance to DNA: when bacterial DNA from microbiota that is not digested by DNASE1L3 directly encounters B cells that are not necessarily restricted by T cell dependence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jo Spencer reports financial support was provided by Wellcome Trust. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The identification of key materials' parameters correlated with the performance can accelerate the development of heterogeneous catalysts and unveil the relevant underlying physical processes. However, the analysis of correlations is often hindered by inconsistent data. Besides, nontrivial, yet unknown relationships may be important, and the intricacy of the various processes may be significant. Here, we tackle these challenges for the CO oxidation catalyzed by perovskites using a combination of rigorous experiments and artificial intelligence. A series of 13 ABO3 (A = La, Pr, Nd, Sm; B = Cr, Mn, Fe, Co) perovskites was synthesized, characterized, and tested in catalysis. To the resulting dataset, we applied the symbolic-regression SISSO approach. We identified an analytical expression correlated with the activity that contains the normalized unit-cell volume, the Pauling electronegativity of the elements A and B, and the ionization energy of the element B. Therefore, the activity is described by crystallographic distortions and by the chemical nature of A and B elements. The generalizability of the identified descriptor is confirmed by the good quality of the predictions for 3 additional ABO3 and of 16 chemically more complex AMn(1-x)B'xO3 (A = La, Pr, Nd; B' = Fe, Co Ni Cu, Zn) perovskites., (© 2024 Wiley‐VCH GmbH.)

Background: Multidisciplinary Shock Teams have improved clinical outcomes for cardiogenic shock, but their implementation costs have not been studied. This study's objective was to compare costs between patients treated with and without a Shock Team and determine if the team's implementation is cost-effective compared with standard of care., Methods: We examined patients with refractory cardiogenic shock treated with or without a Shock Team at a tertiary academic hospital from 2009 to 2018. Real-world hospital data were used to compare costs and outcomes, including survival at discharge, 1-year survival, and quality-adjusted life years gained at 1 year. Incremental cost-effectiveness ratios were calculated over a 1-year time horizon, with parameter uncertainty evaluated through probabilistic sensitivity analysis using 1000 second-order Monte Carlo simulations., Results: The study involved 244 patients, with 123 treated by the Shock Team and 121 receiving standard of care. Patients were predominantly male (77.5%), with a mean age of 58 (18-92) years. The Shock Team approach improved survival rates at hospital discharge and 1-year follow-up (61.0% versus 47.9%; P =0.04 and 55.0% versus 40.5%; P =0.03, respectively). The incremental cost-effectiveness ratio for increases in survival probability at discharge for the multidisciplinary Shock Team compared with standard of care was $102 088. The incremental cost-effectiveness ratio for increases in survival probability at 1-year was estimated at $96 152 and at $127 862 per 1 quality-adjusted life year gained. Probabilistic sensitivity analysis estimates showed that the Shock Team was cost-effective in the majority of simulations using a willingness-to-pay threshold of $150 000, while it was also dominant in almost one-third of the simulations., Conclusions: The Shock Team approach for treating refractory cardiogenic shock may be a cost-effective alternative to traditional standard of care. These findings can help prioritize the implementation of Shock Team initiatives to further improve cardiogenic shock outcomes.

Objective: To review the evaluation process and the implications for Australian health policy of the 2024 external clinical service evaluation of the Queensland Children's Gender Service (QCGS) and its recommendations., Conclusions: Failing to perform a systematic review of the relevant literature, and adhering to discredited and ideologically based guidelines, the Review made recommendations lacking evidentiary support that have major implications for Queensland and other Australian health services. The evaluation report's recommendations reveal eight areas of concern about the clinic's functioning., Competing Interests: DisclosureThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rieske dioxygenases have a long history of being utilized as green chemical tools in the organic synthesis of high-value compounds, due to their capacity to perform the cis-dihydroxylation of a wide variety of aromatic substrates. The practical utility of these enzymes has been hampered however by steric and electronic constraints on their substrate scopes, resulting in limited reactivity with certain substrate classes. Herein, we report the engineering of a widely used member of the Rieske dioxygenase class of enzymes, toluene dioxygenase (TDO), to produce improved variants with greatly increased activity for the cis-dihydroxylation of benzoates. Through rational mutagenesis and screening, TDO variants with substantially improved activity over the wild-type enzyme were identified. Homology modeling, docking studies, molecular dynamics simulations, and substrate tunnel analysis were applied in an effort to elucidate how the identified mutations resulted in improved activity for this polar substrate class. These analyses revealed modification of the substrate tunnel as the likely cause of the improved activity observed with the best-performing enzyme variants., (© 2024 Wiley Periodicals LLC.)

Background: The African Stroke Organization (ASO) in partnership with the University of Central Lancashire's Stroke Research Team launched the Africa-UK Stroke Partnership (AUKSP). AUKSP undertook two (stroke expert and hospital Stroke Unit (SU)) on-line surveys mapping existing capacity and capability to deliver African stroke care., Methods: An on-line expert survey tool was sent to 139 stroke experts in 54 African countries October 2021-March 2022 and the hospital SU survey to 120 hospital SUs (identified from the expert survey) June-October 2022. Both survey tools were prepared according to the World Stroke Organisation's Roadmap for Delivering Quality Stroke Care. Completed responses were exported from Qualtrics into Microsoft excel and were analysed descriptively., Results: Forty-five expert responses and 62 hospital SU responses were analysed, representing 54(87%) public hospitals, 7(11%) private and 1(2%) charitable organization. In both surveys, three main priorities for improvement of stroke services were: a rapid and prompt stroke diagnosis; effective primary and secondary stroke prevention, and acute stroke management. Survey findings suggest that there is a low presence of national stroke surveillance systems and registries, and heterogeneity in availability of diagnostic services, SUs, endovascular treatments, and rehabilitation., Conclusion: Significant gaps exist in Africa's capacity and capability to deliver essential elements of effective and quality stroke care. Tackling these challenges requires urgent and sustained multi-stakeholder action including: government, administrators, policy makers and other partners. Our survey findings highlight key priority areas for multi-stakeholder engagement and crafting of a pragmatic, prioritized and context-sensitive African Stroke Action Plan., Competing Interests: Declaration of competing interest The Authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

β-Lactamases, which hydrolyse β-lactam antibiotics, are key determinants of antibiotic resistance. Predicting the sites and effects of distal mutations in enzymes is challenging. For β-lactamases, the ability to make such predictions would contribute to understanding activity against, and development of, antibiotics and inhibitors to combat resistance. Here, using dynamical non-equilibrium molecular dynamics (D-NEMD) simulations combined with experiments, we demonstrate that intramolecular communication networks differ in three class A SulpHydryl Variant (SHV)-type β-lactamases. Differences in network architecture and correlated motions link to catalytic efficiency and β-lactam substrate spectrum. Further, the simulations identify a distal residue at position 89 in the clinically important Klebsiella pneumoniae carbapenemase 2 (KPC-2), as a participant in similar networks, suggesting that mutation at this position would modulate enzyme activity. Experimental kinetic, biophysical and structural characterisation of the naturally occurring, but previously biochemically uncharacterised, KPC-2 G89D mutant with several antibiotics and inhibitors reveals significant changes in hydrolytic spectrum, specifically reducing activity towards carbapenems without effecting major structural or stability changes. These results show that D-NEMD simulations can predict distal sites where mutation affects enzyme activity. This approach could have broad application in understanding enzyme evolution, and in engineering of natural and de novo enzymes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: The patchy anatomical distribution of atherosclerosis has been attributed to variation in haemodynamic wall shear stress (WSS). The consensus is that low WSS and a high Oscillatory Shear Index (OSI) trigger the disease. We found that atherosclerosis at aortic branch sites correlates threefold better with transverse WSS (transWSS), a metric which quantifies multidirectional near-wall flow. Coronary artery disease has greater clinical significance than aortic disease but computation of WSS metrics is complicated by the substantial vessel motion occurring during each cardiac cycle. Here we present the first comparison of the distribution of atherosclerosis with WSS metrics computed for moving coronary arteries., Methods: Maps of WSS metrics were computed using dynamic geometries reconstructed from angiograms of ten non-stenosed human right coronary arteries (RCAs). They were compared with maps of fatty streak prevalence derived from a previous study of 1852 RCAs., Results: Time average WSS (TAWSS), OSI, transWSS and the cross-flow index (CFI), a non-dimensional form of the transWSS, gave non-significant or significant but low spatial correlations with lesion prevalence. The highest correlation coefficient (0.71) was for the relative residence time (RRT), a metric that decreases with TAWSS and increases with OSI. The coefficient was not changed if RRT was calculated using CFI, which captures multidirectional WSS only, rather than OSI, which encompasses both multidirectional and oscillatory WSS., Conclusion: Contrary to our earlier findings in the aorta, low WSS in combination with highly multidirectional flow correlates best with lesion location in the RCA, explaining approximately half of its anatomical variation., (© 2024. The Author(s).)

Background: With significant advancements in fetal cardiac imaging, patients with complex congenital heart disease (CHD) carrying a high risk for postnatal demise are now being diagnosed earlier. We sought to assess an interdisciplinary strategy for delivering these children in an operating room (OR) adjacent to a cardiac OR for immediate surgery or stabilization. Methods: All children prenatally diagnosed with CHD at risk for immediate postnatal hemodynamic instability and cardiogenic shock who were delivered in the operating room (OR) between 2012 and 2023 in which the senior author was consulted were included. Results: Eight patients were identified. Six (75%) patients were operated on day-of-life zero, all requiring obstructed total anomalous pulmonary venous return (TAPVR) repair. Of these six patients, 2 (33%) required a simultaneous Norwood procedure, 2 (33%) required pulmonary artery unifocalization and modified Blalock-Taussig-Thomas shunt, and 2 (33%) patients had repair of obstructed mixed TAPVR. The remaining 2 patients potentially planned for immediate surgery had nonimmune hydrops fetalis and went into cardiogenic shock at 12 and 72 hours postnatally, requiring a novel Norwood procedure with left-ventricular exclusion for severe aortic/mitral valve insufficiency. The median ventilation and inpatient durations were 19 [IQR: 11-26] days and 41 [IQR: 32-128] days, respectively. Three(38%) patients required one or more in-hospital reoperations. Subsequent staged procedures included Glenn (n = 5), Fontan (n = 3), biventricular repair (n = 2), ventricular assist device placement (n = 1), and heart transplant (n = 1). Median follow-up was 5.7 [IQR:1.3-7.8] years. The five-year postoperative survival was 88% (n = 7/8). Conclusion: While children with these diagnoses have historically had poor survival, the strategy of birth in the OR adjacent to a cardiac OR where emergent surgery is planned is a potentially promising strategy with excellent clinical outcomes. However, this is a high-resource strategy whose feasibility in any program requires thoughtful assessment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Morales is a consultant for Abbott, Inc., Azyio, Inc., Berlin Heart, Inc., CorMatrix, Inc., Peca, Inc., Syncardia, Inc., and Xeltis, Inc. Dr Ashfaq is a consultant for PyrAmes, Inc.

2,3-Dihydroxypropanesulfonate (DHPS) and sulfolactate (SL) are environmentally important organosulfur compounds that play key roles as metabolic currencies in the sulfur cycle. Despite their prevalence, the pathways governing DHPS and SL production remain poorly understood. Here, we study DHPS-3-dehydrogenase from Cupriavidus pinatubonensis ( Cp HpsN), a bacterium capable of utilizing DHPS as a sole carbon source. Kinetic analysis of Cp HpsN reveals a strict preference for R -DHPS, catalyzing its 4-electron oxidation to R -SL, with high specificity for NAD + over NADP + . The 3D structure of Cp HpsN in complex with Zn 2+ , NADH and R -SL, elucidated through X-ray crystallography, reveals a fold akin to bacterial and plant histidinol dehydrogenases with similar coordination geometry around the octahedral Zn 2+ centre and involving the sulfonate group as a ligand. A key residue, His126, distinguishes DHPS dehydrogenases from histidinol dehydrogenases, by structural recognition of the sulfonate substrate of the former. Site-directed mutagenesis pinpoints Glu318, His319, and Asp352 as active-site residues important for the catalytic activity of Cp HpsN. Taxonomic and pathway distribution analysis reveals the prevalence of HpsN homologues within different pathways of DHPS catabolism and across bacterial classes including Alpha-, Beta-, Gamma-, and Deltaproteobacteria and Desulfobacteria, emphasizing its importance in the biogeochemical sulfur cycle., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Background: Nearly one-half of patients admitted with acute decompensated heart failure (ADHF) are discharged with unresolved congestion, elevating rehospitalization risk. This may be due to suboptimal intravenous (IV) loop diuretic dosing, which may be influenced by home oral diuretic dose., Objectives: The objective of this study was to determine the association between: 1) home oral loop diuretic dose and optimal initial IV loop diuretic dosing in ADHF; and 2)receiving optimal initial IV loop diuretic dosing and length of stay and 30-day readmission., Methods: Retrospective analysis of adults admitted to a large U.S. hospital for ADHF on home oral loop diuretics from 1 January 2014 to 21 December 2021. Patients were categorized by home dose: low (≤40 mg furosemide equivalents), medium (>40-80 mg furosemide equivalents), and high (>80 mg furosemide equivalents). Optimal initial IV dosing was considered ≥2 times home oral dosing. Poisson regression models estimated prevalence ratios (CIs) for optimal initial IV loop diuretic dosing., Results: Among 3,269 adults admitted for ADHF (mean age 63 years, 62% male), optimal initial IV dosing occurred in 2,218 (67.9%). The prevalence of optimal initial IV dosing among low, medium, and high home dosing was 95.5%, 59.9%, and 4.0%, respectively. Adjusted prevalence ratios for optimal IV dosing with high and medium home dosing, compared to low, were 0.05 (95% CI: 0.03-0.07) and 0.66 (95% CI: 0.62-0.70), respectively. There was no difference in length of stay or 30-day readmission between optimal and suboptimal initial IV diuretic dosing., Conclusions: Among patients with ADHF, higher home loop diuretic dose was strongly associated with a substantially lower likelihood of optimal initial IV diuretic dosing., Competing Interests: Dr Bress was supported by K24AG080168. James C. Fang has relevant disclosures with AstraZeneca (DELIVER-HF Steering Committee/U.S. National Lead Co-Investigator, PRESERVED-HF DSMB, REALIZE-K DSMB), Amgen (GALACTIC-HF Steering Committee/U.S. National Lead Co-Investigator), and the NIH (TRANSFORM-HF pharmacokinetic substudy). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Shortly after the emergence of newly formed human B cells from bone marrow as transitional cells, they diverge along two developmental pathways that can be distinguished by the level of IgM they express and migratory biases. Here, we propose that differential tissue homing of immature B cell subsets contributes to human lymphoid tissue structure and function., (© 2024 Spencer and Dionisi.)

Background: Within outpatient services, a broad range of innovations are being pursued to better manage care and reduce unnecessary appointments. One of the least-studied innovations is Patient-Initiated Follow-Up, which allows patients to book appointments if and when they need them, rather than follow a standard schedule., Objectives: To use routine national hospital data to identify innovations in outpatient services implemented, in recent years, within the National Health Service in England. To carry out a rapid mixed-methods evaluation of the implementation and impact of Patient-Initiated Follow-Up., Methods: The project was carried out in four sequential workstreams: (1) a rapid scoping review of outpatient innovations; (2) the application of indicator saturation methodology for scanning national patient-level data to identify potentially successful local interventions; (3) interviews with hospitals identified in workstream 2; and (4) a rapid mixed-methods evaluation of Patient-Initiated Follow-Up. The evaluation of Patient-Initiated Follow-Up comprised an evidence review, interviews with 36 clinical and operational staff at 5 National Health Service acute trusts, a workshop with staff from 13 National Health Service acute trusts, interviews with four patients, analysis of national and local data, and development of an evaluation guide., Results: Using indicator saturation, we identified nine services with notable changes in follow-up to first attendance ratios. Of three sites interviewed, two queried the data findings and one attributed the change to a clinical assessment service. Models of Patient-Initiated Follow-Up varied widely between hospital and clinical specialty, with a significant degree of variation in the approach to patient selection, patient monitoring and discharge. The success of implementation was dependent on several factors, for example, clinical condition, staff capacity and information technology systems. From the analysis of national data, we found evidence of an association between greater use of Patient-Initiated Follow-Up and a lower frequency of outpatient attendance within 15 out of 29 specialties and higher frequency of outpatient attendance within 7 specialties. Four specialties had less frequent emergency department visits associated with increasing Patient-Initiated Follow-Up rates. Patient-Initiated Follow-Up was viewed by staff and the few patients we interviewed as a positive intervention, although there was varied impact on individual staff roles and workload. It is important that sites and services undertake their own evaluations of Patient-Initiated Follow-Up. To this end we have developed an evaluation guide to support trusts with data collection and methods., Limitations: The Patient-Initiated Follow-Up evaluation was affected by a lack of patient-level data showing who is on a Patient-Initiated Follow-Up pathway. Engagement with local services was also challenging, given the pressures facing sites and staff. Patient recruitment was low, which affected the ability to understand experiences of patients directly., Conclusions: The study provides useful insights into the evolving national outpatient transformation policy and for local practice. Patient-Initiated Follow-Up is often perceived as a positive intervention for staff and patients, but the impact on individual outcomes, health inequalities, wider patient experience, workload and capacity is still uncertain., Future Research: Further research should include patient-level analysis to determine clinical outcomes for individual patients on Patient-Initiated Follow-Up and health inequalities, and more extensive investigation of patient experiences., Study Registration: This study is registered with the Research Registry (UIN: researchregistry8864)., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 16/138/17) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 38. See the NIHR Funding and Awards website for further award information.

Background: While individual risk factors, including chronic corticosteroid use, alcohol abuse, and smoking, are implicated in osteonecrosis of the femoral head (ONFH), the degree to which multiple risk factors increase risk is unknown. This study aimed to: (1) identify the demographic characteristics of patients who have ONFH; (2) quantify the effects of individual risk factors on ONFH development; (3) quantify the effects of combined risk factors on ONFH development; and (4) determine the prognostic implications of combined risk factors on ONFH development., Methods: This was a retrospective cohort study. A national insurance database was used to study a population of 2,612,383 adult patients who had a 10-year follow-up period. There were 10,233 patients identified who had a diagnosis of ONFH. We identified patients who had chronic corticosteroid use, tobacco use, and/or alcohol abuse and assessed the risk of developing ONFH over a 10-year period. Patients who had individual and multiple risk factors were grouped for comparison, and Chi-square analyses were performed., Results: Higher proportions of patients who had each individual risk factor developed ONFH compared to proportions of patients who did not have risk factors. Patients who had combined risk factors were at greater risk of developing ONFH compared to patients who had no risk factors and those who had single risk factors. Combined risk factors demonstrated multiplicative effects on the development of ONFH: tobacco-alcohol risk ratio (RR) 5.25, corticosteroid-alcohol RR 10.20, tobacco-corticosteroid RR 8.69, and corticosteroid-tobacco-alcohol RR 12.54. Patients who had combined risk factors developed ONFH at younger ages than those who had single risk factors. Kaplan-Meier curve analyses demonstrated worse 10-year hip survival in the setting of combined risk factors., Conclusions: Combined risk factors have a multiplicative effect on the risk of developing of atraumatic ONFH. Orthopaedic surgeons may care for at-risk individuals through modulation of risk factors., Level of Evidence: Retrospective Cohort Study, Level III., (Copyright © 2024 Elsevier Inc. All rights reserved.)

On the basis of historical influenza and COVID-19 forecasts, we found that more than 3 forecast models are needed to ensure robust ensemble accuracy. Additional models can improve ensemble performance, but with diminishing accuracy returns. This understanding will assist with the design of current and future collaborative infectious disease forecasting efforts.

Objective: To present a single-center prospective study of 126 consecutively treated patients who underwent endovascular repair of a thoracoabdominal aortic aneurysm with the physician-modified, nonanatomic-based Unitary Manifold (UM) device., Methods: Data were collected from 126 consecutive all-comer patients treated with the physician-modified, nonanatomic-based UM from 2015 to 2023. Treatment was performed at a single center by a single physician under a Physician Sponsored Investigation Exemption G140207., Results: The UM was indicated for repair of all Crawford extents including juxtarenal, pararenal, and short-neck infrarenal aneurysms (<10 mm) in 126 consecutive patients. Patients were not excluded from the study based on presentation, extent of aneurysm or dissection, or history of a spinal cord event. Patients with a thoracoabdominal aortic aneurysm were categorized by Crawford classification: types I and V (3.3%, n = 4), type II (3.3%, n = 4), type III (1%, n = 1), and type IV (93.3%, n = 117). The type IV classification patients were further categorized with 33 (28.2%) true type IV, 68 (58.1%) pararenal or infrarenal, and 16 (13.7%) with dissection. Technical success was 99.2% (n = 125). The most common major adverse event within both 30 days and 365 days of all patients was respiratory failure (11.9%, n = 15, and 13.5%, n = 17, respectively). One patient (0.8%) experienced persistent paraplegia at 365 days. Reintervention for patients at 365 days was 5.6% (n = 7). Of the 444 branches stented, the primary patency rate was remarkably high as only three patients (2.4%) required reintervention due to loss of limb patency within 365 days. Aneurysm enlargement (≥5 mm) occurred in 1.6% (n = 2) patients, and no patients experienced aneurysm rupture. No patients underwent conversion to open repair. The aneurysm-related mortality at 365 days for all patients was 4.0% (n = 5), whereas all-cause mortality was 16.7% (n = 21). Physician-modified endograft device integrity failure was not observed in any patient., Conclusions: The UM device demonstrated remarkable technical surgical success, treatment success, and device patency rates with very reasonable major adverse events and reintervention rates. This study is the most representative example of the general population in comparison with other studies of off-the-shelf devices, with 126 consecutive all-comer patients with diverse pathologies., Competing Interests: Disclosures A.V. and A.G. are employees of Sanford Health. P.W.K. and J.S. are prior employees of Sanford Health.P.W.K. is the inventor of the Unitary Manifold device. The remaining authors report no conflicts., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: A 45-year-old woman with a history of previously treated left plantar foot melanoma presented with a left thigh mass. Fine needle aspiration findings were concerning for metastatic melanoma (MM). Imaging was remarkable for PET-avidity of both the biopsied thigh mass and of a left posterior knee nodule. The knee nodule was also enhancing on MRI, concerning for a site of metastasis. Resection of the thigh mass and intra-articular nodule was performed. The thigh lesion was positive for MM. The specimen obtained from the knee demonstrated a proliferation of spindle and epithelioid cells associated with focal fibrosis and scattered giant cells with brown pigment, raising the possibility of melanoma metastasis with treatment effect. Additional immunohistochemical studies with anti-SOX10 failed to demonstrate melanoma cells in the lesion. The final diagnosis for the knee nodule was pigmented villonodular synovitis. This case highlights the potential for pigmented villonodular synovitis to mimic MM, requiring additional pathologic analysis to yield an accurate diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Glioblastoma (GBM) is the most common primary brain cancer in adults with a very poor prognosis. Metabolic drivers of tumorigenesis are highly relevant within the central nervous system, where glucose is the critical source of energy. The impact of obesity on survival outcomes in patients with GBM is not well established. This study investigates the prognostic value of body mass index (BMI) in patients diagnosed with GBM., Methods: Adult patients with newly diagnosed GBM treated at Thomas Jefferson University Hospital between January 1, 2008, and December 31, 2022, were included in the study. BMI was calculated using the formula BMI = kg/m 2 . Patients BMI groups were underweight (BMI < 19.00), normal weight (BMI 19.00-24.99), overweight (BMI 25-29.99), and obese (BMI > 30.00). All patients received 60 Gy of radiation therapy with concurrent and adjuvant temozolomide following maximal safe resection. A difference in clinical outcomes of overall survival (OS) and progression-free survival (PFS) were evaluated between the groups using Kaplan-Meier and log-rank tests., Results: A total of 392 patients met inclusion criteria. The median age was 60.3 (range 18.9-86.7), with 144 females and 248 males. Median BMI was 27.0 (Range; 17.7-52.9). Non-overweight GBM patients (BMI < 25.00, OS 2.1 years, CI 1.7-2.4 years) had increased overall survival compared to overweight patients (BMI ≥ 25.00, OS 1.5 years, CI 1.4-1.6 years) (p < 0.001). Patients with MGMT-methylated GBM also had significantly greater OS and PFS compared to MGMT-unmethylated patients (p < 0.001). Non-overweight GBM patients (BMI < 25.00, median PFS 1.5 years, CI 1.3-2.0 years) also had increased progression-free survival compared to overweight patients (BMI ≥ 25.00, median PFS 1.1 years, CI 0.9-1.2 years) (p < 0.001)., Conclusions: Our study indicates normal BMI (19.00-24.99) at the time of GBM diagnosis is a favorable prognostic indicator for overall and progression-free survival. Additional studies are warranted for further analysis of BMI and survival outcomes in GBM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No grants or outside funding was acquired for the completion of this study as well., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fishing is a common recreational activity in the United States, with over 29 million registered fishers. Although not inherently dangerous, commonly seen injuries from fishing include embedded fishhooks and injury from flora and fauna. Emergency department (ED) physicians need a basic understanding of how to treat these less-than-frequent injuries. We present a case report of a patient who presented with a catfish spine lodged in her leg. These spines not only cause puncture wounds but can result in lacerations and venom release as well. Our patient presented 6 hours after the initial injury for spine removal and symptom management. Plain radiographs of the affected extremity demonstrated a 2 cm foreign body consistent with a catfish spine. The wound was expanded, and the spine successfully removed. The patient was discharged on levofloxacin and reported a healing wound without complications nearly 2 weeks after the injury., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To summarize the key recommendations of England's independent inquiry into gender identity services for children and young people (the Cass Review) and to evaluate their relevance to Australian health policy., Conclusions: The Cass Review's findings and recommendations have clear applicability to Australian health policy. As a matter of priority, Australian health authorities need to seriously engage with the Cass Review's findings and recommendations. To not do so will put the health and well-being of vulnerable children and young people at risk., Competing Interests: DisclosureThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AC is affiliated with the Society for Evidence-Based Gender Medicine (SEGM). PC is affiliated with SEGM, Beyond Trans, and is an Advisory Committee Member of Genspect. JS is affiliated with SEGM and Genspect. AA is Deputy Editor of Australasian Psychiatry.

Introduction: Systematic Review and Meta-Analysis (SRMAs) in neurosurgery have significantly increased. With approximately 1 million patients affected by cerebrovascular disease annually, interpreting SRMAs necessitates a systematic approach. The objective of this review is to identify and describe four essential domains for SRMA interpretation., Methods: This review outlines the necessities of reviewing existing literature and methodological frameworks essential for interpreting cerebrovascular neurosurgery SRMAs. Each domain is to accurately assess study design variations, heterogeneity assessment methods, outcome comparability strategies, and the impact of technological advancements and time bias on study outcomes., Results: Study design evaluation distinguishes between randomized controlled trials (RCTs) and non-randomized studies. RCTs provide high internal validity, but as seen in the ARUBA trial, can contain internal flaws that necessitate a deeper understanding before application to clinical practices. Non-randomized studies offer valuable real-world insights. A heterogeneity assessment involves readers and writers accurately using forest plots, Cochrane's Q test, Higgins I² statistics, subgroup analysis, and meta-regressions to understand a study's clinical findings. The expertise thresholds, as in the NASCET trial, significantly impact a study's external validity. Strategies such as the GRADE approach can assist in managing diverse outcome measures. Technological advancements, particularly in endovascular procedures and SRS, influence the accuracy of comparing studies across periods, and thus swiftly outdate older studies, lowering the applicability of SRMAs., Conclusion: Effective interpretation of cerebrovascular neurosurgery SRMAs requires attention to study design, heterogeneity, outcome comparability, and technological advancements. These domains collectively enable evidence-based clinical decision-making and optimized patient care in a dynamic field., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mycobacterium tuberculosis is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. M. tuberculosis DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit M. tuberculosis GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives ( 1 , 2 , 3 , and 8 ), the benzoindole derivative 11 , and the indole derivative 14 . Carbazole derivatives can be considered a new scaffold for M. tuberculosis DNA gyrase ATPase inhibitors. IC 50 values of compounds 8 , 11 , and 14 (0.26, 0.56, and 0.08 μM, respectively) for inhibition of M. tuberculosis DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of M. tuberculosis H37Ra are 25.0, 3.1, and 6.2 μg/mL, respectively, superior to novobiocin (MIC > 100.0 μg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds 8 , 11 , and 14 to M. tuberculosis GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both M. tuberculosis DNA gyrase ATPase activity in vitro and growth of M. tuberculosis bacteria.

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021-22 and 2022-23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021-22 and 12 out of 18 models in 2022-23. Averaging across all forecast targets, the FluSight ensemble is the 2 nd most accurate model measured by WIS in 2021-22 and the 5 th most accurate in the 2022-23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Semiochemicals can be used to manipulate insect behaviour for sustainable pest management strategies, but their high volatility is a major issue for their practical implementation. Inclusion of these molecules within porous materials is a potential solution to this issue, as it can allow for a slower and more controlled release. In this work, we demonstrate that a series of Zr(IV) and Al(III) metal-organic frameworks (MOFs) with channel-type pores enable controlled release of three semiochemicals over 100 days by pore size design, with the uptake and rate of release highly dependent on the pore size. Insight from grand canonical Monte Carlo simulations indicates that this is due to weaker MOF-guest interactions per guest molecule as the pore size increases. These MOFs are all stable post-release and can be reloaded to show near-identical re-release profiles. These results provide valuable insight on the diffusion behaviour of volatile guests in MOFs, and for the further development of porous materials for sustainable agriculture applications., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Mycobacterial glycolipids are important cell envelope structures that drive host-pathogen interactions. Arguably, the most important are lipoarabinomannan (LAM) and its precursor, lipomannan (LM), which are trafficked from the bacterium to the host via unknown mechanisms. Arabinomannan is thought to be a capsular derivative of these molecules, lacking a lipid anchor. However, the mechanism by which this material is generated has yet to be elucidated. Here, we describe the identification of a glycoside hydrolase family 76 enzyme that we term LamH (Rv0365c in Mycobacterium tuberculosis) which specifically cleaves α-1,6-mannoside linkages within LM and LAM, driving its export to the capsule releasing its phosphatidyl-myo-inositol mannoside lipid anchor. Unexpectedly, we found that the catalytic activity of this enzyme is important for efficient exit from stationary phase cultures, potentially implicating arabinomannan as a signal for growth phase transition. Finally, we demonstrate that LamH is important for M. tuberculosis survival in macrophages., (© 2024. The Author(s).)

Objective: Treatment of craniopharyngioma typically entails gross total resection (GTR) or subtotal resection with adjuvant radiation (STR-RT). We analyzed outcomes in adults with craniopharyngioma undergoing GTR versus STR-RT., Methods: This retrospective study enrolled 115 patients with craniopharyngioma in 5 institutions. Patients with STR received postoperative RT with stereotactic radiosurgery or fractionated radiation therapy per institutional preference and ability to spare optic structures., Results: Median age was 44 years (range, 19-79 years). GTR was performed in 34 patients and STR-RT was performed in 81 patients with median follow-up of 78.9 months (range, 1-268 months). For GTR, local control was 90.5% at 2 years, 87.2% at 3 years, and 71.9% at 5 years. For STR-RT, local control was 93.6% at 2 years, 90.3% at 3 years, and 88.4% at 5 years. At 5 years following resection, there was no difference in local control (P = 0.08). Differences in rates of visual deterioration or panhypopituitarism were not observed between GTR and STR-RT groups. There was no difference in local control in adamantinomatous and papillary craniopharyngioma regardless of treatment. Additionally, worse local control was found in patients receiving STR-RT who were underdosed with fractionated radiation therapy (P = 0.03) or stereotactic radiosurgery (P = 0.04)., Conclusions: Good long-term control was achieved in adults with craniopharyngioma who underwent STR-RT or GTR with no significant difference in local control. First-line treatment for craniopharyngioma should continue to be maximal safe resection followed by RT as needed to balance optimal local control with long-term morbidity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Telomerase is the enzyme that lengthens telomeres and is tightly regulated by a variety of means to maintain genome integrity. Several DNA helicases function at telomeres, and we previously found that the Saccharomyces cerevisiae helicases Hrq1 and Pif1 directly regulate telomerase. To extend these findings, we are investigating the interplay between helicases, single-stranded DNA (ssDNA) binding proteins (ssBPs), and telomerase. The yeast ssBPs Cdc13 and RPA differentially affect Hrq1 and Pif1 helicase activity, and experiments to measure helicase disruption of Cdc13/ssDNA complexes instead revealed that Cdc13 can exchange between substrates. Although other ssBPs display dynamic binding, this was unexpected with Cdc13 due to the reported in vitro stability of the Cdc13/telomeric ssDNA complex. We found that the DNA exchange by Cdc13 occurs rapidly at physiological temperatures, requires telomeric repeat sequence DNA, and is affected by ssDNA length. Cdc13 truncations revealed that the low-affinity binding site (OB1), which is distal from the high-affinity binding site (OB3), is required for this intermolecular dynamic DNA exchange (DDE). We hypothesize that DDE by Cdc13 is the basis for how Cdc13 'moves' at telomeres to alternate between modes where it regulates telomerase activity and assists in telomere replication., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The sulfolipid sulfoquinovosyl diacylglycerol (SQDG), produced by plants, algae, and cyanobacteria, constitutes a major sulfur reserve in the biosphere. Microbial breakdown of SQDG is critical for the biological utilization of its sulfur. This commences through release of the parent sugar, sulfoquinovose (SQ), catalyzed by sulfoquinovosidases (SQases). These vanguard enzymes are encoded in gene clusters that code for diverse SQ catabolic pathways. To identify, visualize and isolate glycoside hydrolase CAZY-family 31 (GH31) SQases in complex biological environments, we introduce SQ cyclophellitol-aziridine activity-based probes (ABPs). These ABPs label the active site nucleophile of this enzyme family, consistent with specific recognition of the SQ cyclophellitol-aziridine in the active site, as evidenced in the 3D structure of Bacillus megaterium SQase. A fluorescent Cy5-probe enables visualization of SQases in crude cell lysates from bacteria harbouring different SQ breakdown pathways, whilst a biotin-probe enables SQase capture and identification by proteomics. The Cy5-probe facilitates monitoring of active SQase levels during different stages of bacterial growth which show great contrast to more traditional mRNA analysis obtained by RT-qPCR. Given the importance of SQases in global sulfur cycling and in human microbiota, these SQase ABPs provide a new tool with which to study SQase occurrence, activity and stability., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Introduction: Around 40% of adults have pre-hypertension (120-139/80-89mmHg) increasing their risk of developing hypertension and associated cardiovascular conditions. Guidance on pre-hypertension management focuses on improving lifestyle. Self-monitoring may improve awareness and understanding of blood pressure (BP) for people with pre-hypertension, allowing them to modify their lifestyle risks., Aim: To determine the fidelity to and utility of a home BP self-monitoring regime in people with pre-hypertension., Method: This sub-study is part of a larger prospective, non-randomised feasibility study. Individuals with pre-hypertension were identified via GP records and pharmacy NHS Health Checks in Northwest England. Participants received training for home BP self-monitoring. They were asked to complete two readings (leaving a 5-minute interval) on the first three days of the month for six months, colour-code their readings and take action using a simple algorithm, then send them to the research team within 7 days., Results: Eighty participants (aged 40-79, mean=59) enrolled. The majority were female (n=45, 56%), White British (n=79, 99%), and had not previously monitored their BP (n=55, 69%). Seventy-five (94%) participants completed the training. Sixty-one (81%) received online training and 14 (19%) opted for a face-to-face session. Sixty-one (81%) completed all six months of readings, 51 (68%) also returned them on time. All in-person training participants completed all six months of readings on time. Reasons for non-compliance to the protocol included battery issues, forgetting, and struggling to find a consistent time for readings., Conclusion: Home BP self-monitoring can be feasible and easily implementable for people with pre-hypertension - however, some barriers were identified., (© British Journal of General Practice 2024.)

Finding appropriate image analysis techniques for a particular purpose can be difficult. In the context of the analysis of immunocytochemistry images, where the key information lies in the number of nuclei containing co-localised fluorescent signals from a marker of interest, researchers often opt to use manual counting techniques because of the paucity of available tools. Here, we present the development and validation of the Fluorescence Imaging of Nuclear Staining (FINS) algorithm for the quantification of fluorescent signals from immunocytochemically stained cells. The FINS algorithm is based on a variational segmentation of the nuclear stain channel and an iterative thresholding procedure to count co-localised fluorescent signals from nuclear proteins in other channels. We present experimental results comparing the FINS algorithm to the manual counts of seven researchers across a dataset of three human primary cell types which are immunocytochemically stained for a nuclear marker (DAPI), a biomarker of cellular proliferation (Ki67), and a biomarker of DNA damage (γH2AX). The quantitative performance of the algorithm is analysed in terms of consistency with the manual count data and acquisition time. The FINS algorithm produces data consistent with that achieved by manual counting but improves the process by reducing subjectivity and time. The algorithm is simple to use, based on software that is omnipresent in academia, and allows data review with its simple, intuitive user interface. We hope that, as the FINS tool is open-source and is custom-built for this specific application, it will streamline the analysis of immunocytochemical images., (© 2024. The Author(s).)

Background: The etiology of transcatheter aortic valve (TAV) degeneration is poorly understood, particularly noncalcific mechanisms., Objectives: The authors sought to investigate noncalcific and calcific mechanisms of TAV degeneration and evaluate their impact on leaflet function by bench testing, imaging, and histology., Methods: TAV explants were obtained from the EXPLANT THV registry and clinical institutions. Hydrodynamic assessment was performed using a heart valve pulse duplicator system under physiological conditions. Micro-computed tomography, high-resolution photography, high speed video, and hematoxylin and eosin staining were used to evaluate the morphological appearance, leaflet kinematics, and calcium burden of TAVs., Results: A total of 14 explants were evaluated: 10 self-expanding CoreValve/Evolut TAVs (Medtronic), 3 balloon-expandable SAPIEN 3 TAVs (Edwards Lifesciences), and 1 mechanically expandable Lotus TAV (Boston Scientific). The median patient age at explantation was 73.0 years (Q1-Q3: 64.5-80.0 years), with a time to explantation of 4 years 1 month (1 year 5 months to 4 years 11 months). Six TAV explants were found to have leaflet calcification (162.4 mm 3 ; 58.8-603.0 mm 3 ), and 8 had no calcification detectable by micro-computed tomography and histology. All samples had impaired leaflet kinematics. There was no significant difference in the hydrodynamic mean gradient between calcified (47.2 mm Hg; 26.6-74.1 mm Hg) and noncalcified (27.6 mm Hg; 15.2-36.7 mm Hg; P = 0.28) TAVs. Leaflet calcification had a weak but nonsignificant association with the hydrodynamic mean gradient (r = 0.42; P = 0.14)., Conclusions: TAV function can be severely impacted by noncalcific and calcific mechanisms of tissue degeneration. Importantly, functional stenosis can occur in TAVs in the absence of obvious and significant calcification., Competing Interests: Funding Support and Author Disclosures This work was supported by Medtronic, USA, and the Cardiovascular Translational Laboratory, Canada. Dr Sathananthan is the chief medical officer for Interventional Cardiology Therapies from Boston Scientific; a consultant to Medtronic and Edwards Lifesciences; has received speaking fees from Edwards Lifesciences, and NVT; and has received research support from Medtronic, Edwards Lifesciences, and Vivitro Labs. Mr Nigade, Dr Spencer, and Mr Navarro are employees and shareholders of Medtronic. Dr Meier has received an institutional grant from Edwards Lifesciences. Dr Pirelli is a consultant and receives speakers honoraria from Medtronic and Edwards Lifesciences. Dr Webb is a consultant to and has received research funding from Edwards Lifesciences, Abbott, and ViVitro Labs. Dr Wood is a consultant and receives unrestricted grant support from Medtronic, Edwards Lifesciences, and Abbott Vascular. Dr Lutter is a consultant to Medtronic, Edwards Lifesciences, and Abbott. Dr Puehler is a consultant to Abbott. Dr Tang has received speaker honoraria and served as a physician proctor, consultant, advisory board member, TAVR publications committee member, APOLLO trial screening committee member and IMPACT MR steering committee member for Medtronic, has received speaker honoraria and served as a physician proctor, consultant, advisory board member and TRILUMINATE trial anatomic eligibility and publications committee member for Abbott Structural Heart, has served as an advisory board member for Boston Scientific and JenaValve, a consultant and physician screening committee member for Shockwave Medical, a consultant for NeoChord, Peija Medical and Shenqi Medical Technology, and has received speaker honoraria from Siemens Healthineers. Dr Fukuhara is a consultant for Medtronic, Terumo Aortic, and Artivion. Dr Sellers is a consultant for Medtronic, Edwards Lifesciences, and Anteris; and has received research support from Medtronic, Edwards Lifesciences, Vivitro Labs, and HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been "harvested" by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6')-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dulyayangkul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

DNA gyrases catalyze negative supercoiling of DNA, are essential for bacterial DNA replication, transcription, and recombination, and are important antibacterial targets in multiple pathogens, including Mycobacterium tuberculosis , which in 2021 caused >1.5 million deaths worldwide. DNA gyrase is a tetrameric (A 2 B 2 ) protein formed from two subunit types: gyrase A (GyrA) carries the breakage-reunion active site, whereas gyrase B (GyrB) catalyzes ATP hydrolysis required for energy transduction and DNA translocation. The GyrB ATPase domains dimerize in the presence of ATP to trap the translocated DNA (T-DNA) segment as a first step in strand passage, for which hydrolysis of one of the two ATPs and release of the resulting inorganic phosphate is rate-limiting. Here, dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations of the dimeric 43 kDa N-terminal fragment of M. tuberculosis GyrB show how events at the ATPase site (dissociation/hydrolysis of bound nucleotides) are propagated through communication pathways to other functionally important regions of the GyrB ATPase domain. Specifically, our simulations identify two distinct pathways that respectively connect the GyrB ATPase site to the corynebacteria-specific C-loop, thought to interact with GyrA prior to DNA capture, and to the C-terminus of the GyrB transduction domain, which in turn contacts the C-terminal GyrB topoisomerase-primase (TOPRIM) domain responsible for interactions with GyrA and the centrally bound G-segment DNA. The connection between the ATPase site and the C-loop of dimeric GyrB is consistent with the unusual properties of M. tuberculosis DNA gyrase relative to those from other bacterial species.

Background: New cancer diagnoses are associated with employment decrease, workplace absenteeism, and attributable costs to employers., Objective: To estimate the workplace productivity loss in the year following a new diagnosis of early-, intermediate-, or advanced-stage hepatocellular carcinoma (HCC) in commercially insured US adults., Methods: We conducted a retrospective cohort study using Merative MarketScan commercial claims to identify incident HCC diagnoses from 2010 to 2020. Patients were stratified into early-, intermediate-, or advanced-stage cohorts based on presence of secondary malignancy codes or first treatment received. Mean workdays lost and attributable cost in the year following a new diagnosis were calculated using the Kaplan-Meier sample averages to account for censoring. An exploratory analysis was conducted on subgroups in the early and advanced cohorts to assess productivity loss in patients with and without treatment., Results: Mean workdays lost in the year following a new HCC diagnosis among the early, intermediate, and advanced cohorts was 22.6 days (95% CI = 16.0-29.8), 17.4 days (95% CI = 11.9-23.2), and 19.5 days (95% CI = 15.6-23.6), respectively. Corresponding indirect costs were $6,031(95% CI = $4,270-$7,953), $4,644 (95% CI = $3,176-$6,192), and $5,204 (95% CI = $4,163-$6,298). Early-stage patients without a liver transplant and advanced-stage patients who received systemic therapy had 19.7 (95% CI = 12.7-27.4) and 22.0 (95% CI = 16.6-27.7) mean workdays lost, respectively., Conclusions: Productivity loss varies by stage and appears to be higher in early-stage patients who receive more intensive treatments in the first year following a new HCC diagnosis.

Background and Objectives: The Friedreich ataxia (FRDA) scientific community needs access to patient-centered outcome measures that satisfy regulatory guidelines and are capable of tracking clinically meaningful changes in FRDA disease burden. The objective of this research was to develop a novel, disease-specific caregiver-reported outcome measure for use in FRDA research and clinical care., Methods: In prior work, we conducted qualitative interviews and a cross-sectional study of FRDA caregivers and patients to determine the symptoms of greatest importance to individuals with FRDA. We designed the Friedreich Ataxia Caregiver-Reported Health Index (FACR-HI) to serially measure the symptoms of greatest importance to patients and utilized factor analysis, beta testing, reliability testing, and cross-sectional subgroup analysis to further evaluate and optimize this disease-specific outcome measure., Results: The FACR-HI was designed to measure total disease burden and disease burden in 18 symptomatic domains. The FACR-HI total score demonstrated high internal consistency (Cronbach's α = 0.98) and test-retest reliability (intraclass correlation coefficient = 0.96). Beta interview participants found the FACR-HI to be highly relevant, comprehensive, and easy to use. FACR-HI total and subscale scores were associated with functional staging for ataxia scores and speech impairment., Discussion: Initial evaluation of the FACR-HI supports its content validity, test-retest reliability, and construct validity as a caregiver-reported outcome measure for assessing how pediatric individuals with FRDA feel and function. The FACR-HI provides a potential mechanism to quantify changes in multifactorial FRDA disease burden during future clinical trials., Competing Interests: S. Subramony receives research support from the NIH, FDA, Wyck, Friedreich’s Ataxia Research Alliance, Muscular Dystrophy Association, Facioscapulohumeral Muscular Dystrophy Society, National Ataxia Foundation, Reata, PTC, Retrotope, Biohaven, Takeda, Acceleron, Pharnext, Avidity, and Reneo. He has provided consultation or served on advisory boards for Dyne, Avidity, Reata, and AveXis; D.R. Lynch receives grant support from the NIH, FDA, Friedreich’s Ataxia Research Alliance, Reata Pharmaceuticals, Retrotope, PTC Therapeutics, and Design Pharmaceuticals; and C.R. Heatwole receives royalties for the use of multiple disease-specific instruments. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, Neurocrine Biosciences, Sanofi, Lupin Pharmaceuticals, and the Marigold Foundation. He receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Sanofi, Lupin Pharmaceuticals, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, the Amyotrophic Lateral Sclerosis Association, the University of Miami, Novartis Pharmaceuticals Corporation, and the Michael J. Fox Foundation. He is the director of the University of Rochester's Center for Health and Technology. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Background: Schwannomas are benign peripheral nerve sheath tumors arising from myelinating Schwann cells. Although macrocystic changes are regularly encountered in schwannoma variants such as vestibular nerve tumors, they are exceedingly rare among spinal neoplasms., Methods: Case report and systematic review of 4 databases (Ovid Medline, PubMed, Science Direct, and SCOPUS) from inception to present. All peer-reviewed publications reporting intradural cystic thoracic schwannoma were included., Results: We identified 8 publications documenting 9 cases of cystic thoracic schwannoma. Four were female, 5 male; median age was 41 years (range, 27-80). Presentations ranged from incidental to pain, sensory changes, lower extremity paresis, or bowel/bladder dysfunction. Characteristic radiographic findings included T1 hypointensity, T2 hyperintensity, and cord effacement or compression. The present case followed a similar pattern: a 52-year-old male presented with worsening bilateral lower extremity weakness, low back pain, and gait dysfunction, worsening over 3 days. Examination also revealed decreased left lower extremity sensation. Imaging identified a well-delineated intradural, extramedullary macrocystic extending over T7-T10. The patient underwent a laminectomy resulting in complete tumor resection and restoration of intact neurologic function. Final pathology confirmed benign cystic schwannoma., Conclusions: Macrocystic thoracic schwannomas are exceedingly rare and lack a comprehensive scheme for clinical classification of their natural history and pathogenesis. We report the 10th case of such a schwannoma, and the first associated systematic review. Although macrocystic thoracic schwannomas are not frequently encountered, accurate diagnosis and appropriate neurosurgical treatment is critical in these vulnerable patients, given the opportunity for excellent functional outcomes following neurosurgical treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

School reopenings in 2021 and 2022 coincided with the rapid emergence of new SARS-CoV-2 variants in the United States. In-school mitigation efforts varied, depending on local COVID-19 mandates and resources. Using a stochastic age-stratified agent-based model of SARS-CoV-2 transmission, we estimate the impacts of multiple in-school strategies on both infection rates and absenteeism, relative to a baseline scenario in which only symptomatic cases are tested and positive tests trigger a 10-day isolation of the case and 10-day quarantine of their household and classroom. We find that monthly asymptomatic screening coupled with the 10-day isolation and quarantine period is expected to avert 55.4% of infections while increasing absenteeism by 104.3%. Replacing quarantine with test-to-stay would reduce absenteeism by 66.3% (while hardly impacting infection rates), but would require roughly 10-fold more testing resources. Alternatively, vaccination or mask wearing by 50% of the student body is expected to avert 54.1% or 43.1% of infections while decreasing absenteeism by 34.1% or 27.4%, respectively. Separating students into classrooms based on mask usage is expected to reduce infection risks among those who wear masks (by 23.1%), exacerbate risks among those who do not (by 27.8%), but have little impact on overall risk. A combined strategy of monthly screening, household and classroom quarantine, a 50% vaccination rate, and a 50% masking rate (in mixed classrooms) is expected to avert 81.7% of infections while increasing absenteeism by 90.6%. During future public health emergencies, such analyses can inform the rapid design of resource-constrained strategies that mitigate both public health and educational risks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC., Methods: Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5., Results: Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted., Conclusions: This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated., Trial Registration: Jefferson IRB#20976, approved 2/17/21., (© 2024. The Author(s).)

Intestinal homeostasis is maintained by the response of gut-associated lymphoid tissue to bacteria transported across the follicle associated epithelium into the subepithelial dome. The initial response to antigens and how bacteria are handled is incompletely understood. By iterative application of spatial transcriptomics and multiplexed single-cell technologies, we identify that the double negative 2 subset of B cells, previously associated with autoimmune diseases, is present in the subepithelial dome in health. We show that in this location double negative 2 B cells interact with dendritic cells co-expressing the lupus autoantigens DNASE1L3 and C1q and microbicides. We observe that in humans, but not in mice, dendritic cells expressing DNASE1L3 are associated with sampled bacteria but not DNA derived from apoptotic cells. We propose that fundamental features of autoimmune diseases are microbiota-associated, interacting components of normal intestinal immunity., (© 2024. The Author(s).)

Improving patient care and advancing scientific discovery requires responsible sharing of research data, healthcare records, biosamples, and biomedical resources that must also respect applicable use conditions. Defining a standard to structure and manage these use conditions is a complex and challenging task. This is exemplified by a near unlimited range of asset types, a high variability of applicable conditions, and differing applications at the individual or collective level. Furthermore, the specifics and granularity required are likely to vary depending on the ultimate contexts of use. All these factors confound alignment of institutional missions, funding objectives, regulatory and technical requirements to facilitate effective sharing. The presented work highlights the complexity and diversity of the problem, reviews the current state of the art, and emphasises the need for a flexible and adaptable approach. We propose Digital Use Conditions (DUC) as a framework that addresses these needs by leveraging existing standards, striking a balance between expressiveness versus ambiguity, and considering the breadth of applicable information with their context of use., (© 2024. The Author(s).)

Myriad policy, ethical and legal considerations underpin the sharing of biological resources, implying the need for standardised and yet flexible ways to digitally represent diverse 'use conditions'. We report a core lexicon of terms that are atomic, non-directional 'concepts of use', called Common Conditions of use Elements. This work engaged biobanks and registries relevant to the European Joint Programme for Rare Diseases and aimed to produce a lexicon that would have generalised utility. Seventy-six concepts were initially identified from diverse real-world settings, and via iterative rounds of deliberation and user-testing these were optimised and condensed down to 20 items. To validate utility, support software and training information was provided to biobanks and registries who were asked to create Sharing Policy Profiles. This succeeded and involved adding standardised directionality and scope annotations to the employed terms. The addition of free-text parameters was also explored. The approach is now being adopted by several real-world projects, enabling this standard to evolve progressively into a universal basis for representing and managing conditions of use., (© 2024. The Author(s).)

Reading morphologically complex words requires analysis of their morphemic subunits (e.g., play + er); however, the positional constraints of morphemic processing are still little understood. The current study involved three unprimed lexical decision experiments to directly compare the positional encoding of stems and affixes during reading and to investigate the role of semantics during the position encoding of morphemes. Experiment 1 revealed that transposed compound words were harder to reject than their controls (e.g., dreamday vs. shadeday), whereas there was no difference between transposed suffixed words and their controls (e.g., fulpain vs. adepain). Experiment 2 replicated the results for transposed compound words of the first experiment and further showed that there was no difference between transposed prefixed words and their controls (e.g., qualifydis vs. qualifymis). Experiment 3 investigated the role of semantic transparency in morpheme transposition effects and revealed a larger morpheme transposition effect for semantically transparent transposed compound words (e.g., cuptea vs. taptea) than for semantically opaque transposed compound words (e.g., linedead vs. deskdead). These results bring to light important differences in the positional encoding of stems and affixes, suggesting that prefixes and suffixes are recognized in a position-dependent manner compared to the position-independent encoding of embedded stems and that morpheme transposition effects are guided by semantics. The current findings call for more clearly specified theoretical models of visual word recognition that reflect the distinct positional constraints of stems and affixes, as well as the influence of semantics on morphological processing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).